miRNA成熟相关基因DICER、DROSHA、RAN基因多态性与不明原因复发流产的相关性研究
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摘要
目的探讨miRNA成熟关键基因DICER、DROSHA和RAN的基因多态性与女性复发流产的相关性。方法收集2013年6月至2015年12月于四川大学华西第二医院就诊的不明原因复发流产(URSA)患者共217例,至少有1次生育史的育龄妇女为正常对照组390例,对照组为同期进行体检和孕前检查育龄妇女。采用病例对照研究的方法,应用PCR-限制性片段长度多态性技术检测miRNA成熟过程中关键基因DICER rs3742330、DROSHArs10719和RAN rs14035单核苷酸多态性。结果 DICERrs3742330,DROSHArs10719和RANrs14035各等位基因和基因型频率在URSA组和对照组差异无统计学意义(P>0.05)。联合分析发现,DICERrs3742330/DROSHArs10719GG/TT+TC协同会增加复发流产的风险(OR=1.657,95%CI=1.006~2.731,P=0.047)。虽然DICERrs3742330/RANrs14035GG/TT+TC在URSA组较对照组增高,但差异无统计学意义(OR=1.977,95%CI=0.956~4.087,P=0.066),而DROSHA10719/RAN14035TT+TC/TT+TC与复发流产无相关性(OR=0.958,95%CI=0.679~1.353,P=0.808)。结论DICERrs3742330联合DROSHA rs10719可能与URSA相关。
Objective To explore the association between polymorphisms of miRNA biogenesis related gene DICER,DROSHA,RANand unexplained recurrent spontaneous abortion(URSA)in Chinese women.MethodsWe recruited 217 patients with URSA(URSA group)and 390 healthy controls who were fertile women with history of more than one successful pregnancy outcome(control group)from June 2013 to December 2015 in the West China Second University Hospital of Sichuan University.The control group was recruited from regular physical examination and prepregnancy check for women of childbearing age during the same period.A case-control study was performed to analyze polymorphism of miRNA machinery genes,including DICER rs3742330,DROSHA rs10719,RAN rs14035,by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)assay.Results The frequencies of genotypes and alleles of DICER rs3742330,DROSHA rs10719,and RAN rs14035 showed no difference between URSA patients and control group(all P >0.05).DICER rs3742330/DROSHArs10719 GG/TC+TT combinations were synergistically associated with increased URSA risk[odds ratio(OR)=1.657,95% confidence interval(CI)=1.006-2.731,P=0.047].Although DICER rs3742330/RAN rs14035 GG/TT+TC combinations was significantly higher in the URSA group than in the control group,there was no statistical significance(OR=1.977,95%CI=0.956-4.087,P=0.066).However,DROSHA10719/RAN14035 TT+TC/TT+TC had no significant correlation with URSA(OR=0.958,95%CI=0.679-1.353,P=0.808).Conclusion Our study demonstrated the relationship between URSA development and combined genotypeof DICERrs3742330/DROSHArs10719 GG/TC+TT.
Objective To explore the association between polymorphisms of miRNA biogenesis related gene DICER,DROSHA,RANand unexplained recurrent spontaneous abortion(URSA)in Chinese women.MethodsWe recruited 217 patients with URSA(URSA group)and 390 healthy controls who were fertile women with history of more than one successful pregnancy outcome(control group)from June 2013 to December 2015 in the West China Second University Hospital of Sichuan University.The control group was recruited from regular physical examination and prepregnancy check for women of childbearing age during the same period.A case-control study was performed to analyze polymorphism of miRNA machinery genes,including DICER rs3742330,DROSHA rs10719,RAN rs14035,by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)assay.Results The frequencies of genotypes and alleles of DICER rs3742330,DROSHA rs10719,and RAN rs14035 showed no difference between URSA patients and control group(all P >0.05).DICER rs3742330/DROSHArs10719 GG/TC+TT combinations were synergistically associated with increased URSA risk[odds ratio(OR)=1.657,95% confidence interval(CI)=1.006-2.731,P=0.047].Although DICER rs3742330/RAN rs14035 GG/TT+TC combinations was significantly higher in the URSA group than in the control group,there was no statistical significance(OR=1.977,95%CI=0.956-4.087,P=0.066).However,DROSHA10719/RAN14035 TT+TC/TT+TC had no significant correlation with URSA(OR=0.958,95%CI=0.679-1.353,P=0.808).Conclusion Our study demonstrated the relationship between URSA development and combined genotypeof DICERrs3742330/DROSHArs10719 GG/TC+TT.
引文
[1]陈美佳,吕福通,黄霈,等.327对自然流产夫妇的染色体核型分析.中华医学遗传学杂志,2015,32(1):131-132.
[2]李平,朱伟杰.DICER基因在女性生殖中的作用及研究进展.中华医学遗传学杂志,2011,28(3):275-278.
[3]ROMERO Y,MEIKAR O,PAPAIOANNOU MD,et al.Dicer1depletion in male germ cells leads to infertility due to cumulative meiotic and spermiogenic defects.PLoS One,2011,6(10):e25241[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0025241.
[4]HAWKINS SM,ANDREU-VIEYRA CV,KIM TH,et al.Dysregulation of uterine signaling pathways in progesterone receptor-Cre knockout of dicer.Mol Endocrinol,2012,26(9):1552-1566.
[5]FAN P,CHEN Z,TIAN P,et al.miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.PLoS One,2013,8(4):e60888[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0060888.
[6]AKDELI N,RIEMANN K,WESTPHAL J,et al.A 3′UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like kinase 1.Mol Cancer,2014,13:87[2017-03-11].https://doi.org/10.1186/1476-4598-13-87.
[7]JUNG YW,JEON YJ,RAH H,et al.Genetic variants in microRNA machinery genes are associate with idiopathic recurrent pregnancy loss risk.PLoS One,2014,9(4):e95803[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0105743
[8]ZIMMERMANN C,ROMERO Y,WARNEFORS M,et al.Germ cell-specific targeting of DICER or DGCR8revealsa novel role for endo-siRNAs in the progression of mammalian spermatogenesis and male fertility.PLoS One,2014,9(9):e107023[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0107023.
[9]陈良榉,杨明,陈艳,等.miR-15b在内皮细胞的功能及其与血管相关性疾病的关系.遗传,2015,37(2),121-127.
[10]CHO SH,KO JJ,KIM JO,et al.3′-UTR polymorphisms in the miRNA machinery genes DROSHA,DICER1,RAN,and XPO5 are associated with colorectal cancer risk in a korean population.PLoS One,2015,10(7):e0131125[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0131125.
[11]PERSSON H,KVIST A,REGO N,et al.Identification of new micro-RNAs in paired normal and tumor breast tissue suggests a dual role for the ERBB2/Her2gene.Cancer Res,2011,71(1):78-86.
[12]FRIEDLANDER MR,MACKOWIAK SD,LI N,et al.miRDeep2accurately identifies known and hundreds of novel microRNA genes in seven animal clades.Nucleic Acids Res,2012,40(1):37-52.
[13]ZHAO Y,DU Y,ZHAO S.et al.Single-nucleotide polymorphisms of microRNA processing machinery genes and risk of colorectal cancer.Onco Targets Ther,2015,8:421-425.
[14]XIE Y,WANG Y,ZHAO Y,et al.Single-nucleotide polymorphisms of microRNA processing machinery genes are associated with risk for gastric cancer.Onco Targets Ther,2015,8:567-571.
[15]KIM MN,KIM JO,LEE SM,et al.Variation in the dicer and RAN genes are associated with survival in patients with hepatocellular carcinoma.PLoS One,2016,11(9):e0162279[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0162279.
[16]符梅,徐克惠,叶俊杰,等.MiRNA成熟关键基因DROSHA和DICER的多态性与无精症的相关性.中华医学遗传学杂志,2016,33(3):365-368.
[17]ZHOU Y,WANG J,LU X,et al.Evaluation of six SNPs of microRNA machinery genes and risk of schizophrenia.J Mol Neurosci,2013,49(3):594-599.
[18]HAN Y,LIU Y,GUI Y,et al.Inducing cell proliferation inhibition and apoptosis via silencing Dicer,Drosha,and Exportin 5in urothelialcarcinoma of the bladder.J Surg Oncol,2013,107(2):201-205.
[19]DREUSSI E,PUCCIARELLI S,PAOLI A,et al.Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients.Oncotarget,2016,7(15):19781-19793.
[20]YUAN L,CHU H,WANG M,et al.Genetic variation in DROSHA 3′UTR regulated by hsa-miR-27bis associated with bladder cancer risk.PLoS One,2013,8(11):e81524[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0081524.
[2]李平,朱伟杰.DICER基因在女性生殖中的作用及研究进展.中华医学遗传学杂志,2011,28(3):275-278.
[3]ROMERO Y,MEIKAR O,PAPAIOANNOU MD,et al.Dicer1depletion in male germ cells leads to infertility due to cumulative meiotic and spermiogenic defects.PLoS One,2011,6(10):e25241[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0025241.
[4]HAWKINS SM,ANDREU-VIEYRA CV,KIM TH,et al.Dysregulation of uterine signaling pathways in progesterone receptor-Cre knockout of dicer.Mol Endocrinol,2012,26(9):1552-1566.
[5]FAN P,CHEN Z,TIAN P,et al.miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.PLoS One,2013,8(4):e60888[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0060888.
[6]AKDELI N,RIEMANN K,WESTPHAL J,et al.A 3′UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like kinase 1.Mol Cancer,2014,13:87[2017-03-11].https://doi.org/10.1186/1476-4598-13-87.
[7]JUNG YW,JEON YJ,RAH H,et al.Genetic variants in microRNA machinery genes are associate with idiopathic recurrent pregnancy loss risk.PLoS One,2014,9(4):e95803[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0105743
[8]ZIMMERMANN C,ROMERO Y,WARNEFORS M,et al.Germ cell-specific targeting of DICER or DGCR8revealsa novel role for endo-siRNAs in the progression of mammalian spermatogenesis and male fertility.PLoS One,2014,9(9):e107023[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0107023.
[9]陈良榉,杨明,陈艳,等.miR-15b在内皮细胞的功能及其与血管相关性疾病的关系.遗传,2015,37(2),121-127.
[10]CHO SH,KO JJ,KIM JO,et al.3′-UTR polymorphisms in the miRNA machinery genes DROSHA,DICER1,RAN,and XPO5 are associated with colorectal cancer risk in a korean population.PLoS One,2015,10(7):e0131125[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0131125.
[11]PERSSON H,KVIST A,REGO N,et al.Identification of new micro-RNAs in paired normal and tumor breast tissue suggests a dual role for the ERBB2/Her2gene.Cancer Res,2011,71(1):78-86.
[12]FRIEDLANDER MR,MACKOWIAK SD,LI N,et al.miRDeep2accurately identifies known and hundreds of novel microRNA genes in seven animal clades.Nucleic Acids Res,2012,40(1):37-52.
[13]ZHAO Y,DU Y,ZHAO S.et al.Single-nucleotide polymorphisms of microRNA processing machinery genes and risk of colorectal cancer.Onco Targets Ther,2015,8:421-425.
[14]XIE Y,WANG Y,ZHAO Y,et al.Single-nucleotide polymorphisms of microRNA processing machinery genes are associated with risk for gastric cancer.Onco Targets Ther,2015,8:567-571.
[15]KIM MN,KIM JO,LEE SM,et al.Variation in the dicer and RAN genes are associated with survival in patients with hepatocellular carcinoma.PLoS One,2016,11(9):e0162279[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0162279.
[16]符梅,徐克惠,叶俊杰,等.MiRNA成熟关键基因DROSHA和DICER的多态性与无精症的相关性.中华医学遗传学杂志,2016,33(3):365-368.
[17]ZHOU Y,WANG J,LU X,et al.Evaluation of six SNPs of microRNA machinery genes and risk of schizophrenia.J Mol Neurosci,2013,49(3):594-599.
[18]HAN Y,LIU Y,GUI Y,et al.Inducing cell proliferation inhibition and apoptosis via silencing Dicer,Drosha,and Exportin 5in urothelialcarcinoma of the bladder.J Surg Oncol,2013,107(2):201-205.
[19]DREUSSI E,PUCCIARELLI S,PAOLI A,et al.Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients.Oncotarget,2016,7(15):19781-19793.
[20]YUAN L,CHU H,WANG M,et al.Genetic variation in DROSHA 3′UTR regulated by hsa-miR-27bis associated with bladder cancer risk.PLoS One,2013,8(11):e81524[2017-02-08].http://dx.doi.org/10.1371/journal.pone.0081524.